title: Phosphorylation of paxillin confers cisplatin resistance in non-small cell lung cancer via activating ERK-mediated Bcl-2 expression.
abstract: Paxillin (PXN) is required for receptor tyrosine kinase-mediated ERK activation, and the activation of the Raf/MEK/ERK cascade has been linked with Bcl-2 expression. We hypothesized that phosphorylation of PXN by the EGFR/Src pathway might contribute to cisplatin resistance via increased Bcl-2 expression. We show that cisplatin resistance was dependent on PXN expression, as evidenced by PXN overexpression in TL-13 and TL-10 cells and PXN knockdown in H23 and CL1-5 cells. Specific inhibitors of signaling pathways indicated that the phosphorylation of PXN at Y118 and Y31 via the Src pathway was responsible for cisplatin resistance. We further demonstrated that ERK activation was also dependent on this PXN phosphorylation. Bcl-2 transcription was upregulated by phosphorylated PXN-mediated ERK activation via increased binding of phosphorylated CREB to the Bcl-2 promoter. A subsequent increase in Bcl-2 levels by a PXN/ERK axis was responsible for the resistance to cisplatin. Animal models further confirmed the findings of in vitro cells indicating that xenograft tumors induced by TL-13-overexpressing cells were successfully suppressed by cisplatin combined with Src or ERK inhibitor compared with treatment of cisplatin, Src inhibitor or ERK inhibitor alone. A positive correlation of phosphorylated PXN with phosphorylated ERK and Bcl-2 was observed in lung tumors from NSCLC patients. Patients with tumors positive for PXN, phosphorylated PXN, phosphorylated ERK and Bcl-2 more commonly showed a poorer response to cisplatin-based chemotherapy than did patients with negative tumors. Collectively, PXN phosphorylation might contribute to cisplatin resistance via activating ERK-mediated Bcl-2 transcription. Therefore, we suggest that Src or ERK inhibitor might be helpful to improve the sensitivity for cisplatin-based chemotherapy in NSCLC patients with PXN-positive tumors.
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: D-W
authors.initials: DW
authors.lastname: Wu
authors.affiliation: Department of Internal Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
authors.forename: T-C
authors.initials: TC
authors.lastname: Wu
authors.affiliation: 1] Division of Thoracic Surgery, Buddhist Tzu Chi Taichung General Hospital, Taichung, Taiwan, ROC [2] College of Medicine, Tzu Chi University, Hualien, Taiwan, ROC.
authors.forename: J-Y
authors.initials: JY
authors.lastname: Wu
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: Y-W
authors.initials: YW
authors.lastname: Cheng
authors.affiliation: Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taichung, Taiwan, ROC.
authors.forename: Y-C
authors.initials: YC
authors.lastname: Chen
authors.affiliation: Department of Thoracic Surgery, Taichung Veteran General Hospital, Taichung, Taiwan, ROC.
authors.forename: M-C
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Department of Surgery, China Medical University Hospital, Taichung, Taiwan, ROC.
authors.forename: C-Y
authors.initials: CY
authors.lastname: Chen
authors.affiliation: Graduate Institute of Cancer Biology and Drug Discovery, Taipei Medical University, Taipei, Taiwan, ROC.
authors.forename: H
authors.initials: H
authors.lastname: Lee
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001562:Benzimidazoles / Q000008:administration & dosage / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage* / Q000627:therapeutic use; D000069439:Dasatinib; D019008:Drug Resistance, Neoplasm; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008819:Mice, Nude; D051419:Paxillin / Q000378:metabolism*; D010766:Phosphorylation; D011743:Pyrimidines / Q000008:administration & dosage / Q000627:therapeutic use; D013844:Thiazoles / Q000008:administration & dosage / Q000627:therapeutic use; D023041:Xenograft Model Antitumor Assays
chemical_list: C517975:AZD 6244; D000970:Antineoplastic Agents; D001562:Benzimidazoles; D051419:Paxillin; D011743:Pyrimidines; D013844:Thiazoles; D002945:Cisplatin; D000069439:Dasatinib